Midostaurin Shows Promise in Advanced Mastocytosis Trial

Alessandro Riva

The multikinase inhibitor midostaurin (PKC412) demonstrated an overall response rate (ORR) of 60% in patients with advanced systemic mastocytosis, according to phase II findings published in The New England Journal of Medicine.¹

“Patients with advanced [systemic mastocytosis] are part of a very small, highly underserved community that has suffered from a lack of medical innovation for many years,” said Alessandro Riva, global head, Oncology Development and Medical Affairs, Novartis Oncology, in a statement. “Novartis is proud to have developed a treatment that shows benefit for these patients, and is now working with regulatory authorities to make midostaurin available as quickly as possible.”

Systemic mastocytosis is a myeloid neoplasm that affects approximately 8000 individuals in the United States, and is caused by an abnormal buildup of mast cells in bone marrow, skin, and other organs. Patients with advanced systemic mastocytosis typically live a median of less than 6 months to 3.5 years, and there are no FDA-approved treatments for the majority of patients.

In the trial, 116 patients received 100 mg of oral midostaurin twice daily, though 89 were included in the primary efficacy population due to mastocytosis-related organ data. The 89 individuals were classified by disease subtype: 16 had aggressive systemic mastocytosis (18%), 57 had systemic mastocytosis with an associated hematologic neoplasm (64%) and 16 had mast-cell leukemia (18%). Patients were also classified according to KIT D816 mutation status: 77 were positive (87%), 10 were negative (11%), and 2 had unknown status (2%).

In total, 53 patients experienced a major or partial response, equating to a 60 percent ORR. The ORR were similar between subtypes: 12 of 16 patients with aggressive systemic mastocytosis (75%), 33 of 57 patients with systemic mastocytosis with an associated hematologic neoplasm (58%), and 8 of 16 patients with mast-cell leukemia (50%). The overall duration of response among all patients on the trial was 24.1 months. Response rates were also similar, the study authors noted, regardless KIT D816V mutation status and previous treatment.

In the primary efficacy population, median overall survival (OS) was 28.7 months (95% CI, 18.1-not estimated) and 33.9 months (95% CI, 20.3-45.5) in the intent-to-treat population. The longer median OS in the intent-to-treat population, the authors noted, was due to the inclusion of 27 patients who could not be evaluated for response.

Among patients with aggressive systemic mastocytosis, the median OS was not reached (95% CI, 28.7 months-not estimated). OS was 20.7 months (95% CI, 16.0-44.4) among patients with systemic mastocytosis with an associated hematologic neoplasm and 9.4 months (95% CI, 7.5-not estimated) among patients with mast-cell leukemia. Forty-eight patients were alive at time of data cutoff.

The median progression-free survival (PFS) was 14.1 months in the primary efficacy population. However, it was longer among patients with aggressive disease than among patients with systemic mastocytosis with an associated hematologic neoplasm (11.0 months) and patients with mast-cell leukemia (11.3 months).

A post hoc analysis showed that the median OS was significantly longer among patients who had a response than among those without a response (44.4 months [95% CI, 20.3-not estimated] vs 15.4 months [95% CI, 7.5-not estimated]; HR, 0.42; P = 0.005).

“These data show clear disease and symptom improvement with oral midostaurin treatment across a range of study participants who were reflective of the heterogeneity of this disease,” senior study author Andreas Reiter, a professor from the University of Heidelberg in Germany, said in a statement. “If approved, midostaurin will offer patients a much needed treatment option.”

Frequently reported adverse events across the study population included nausea, vomiting, diarrhea, and peripheral edema. Nausea occurred in 92 patients (79%), vomiting in 77 patients (66%), diarrhea in 63 patients (54%), and peripheral edema in 40 patients (34%).

There were lower rates of grade 3/4 events observed: 6% nausea, 6% vomiting, 8% diarrhea, and 4% peripheral edema.

The authors noted that the trial provided initial evidence of midostaurin's efficacy and benefit for patients with regard to reversing organ damage, decreasing splenomegaly, and improving quality of life, among others.

“Future studies are warranted to evaluate midostaurin in combination with other drugs and in the peritransplantation setting in patients with advanced systemic mastocytosis, or as monotherapy in patients with indolent systemic mastocytosis with refractory symptoms,” the authors wrote.

Gotlib J, Hanneke CKN, George TI, et al. Efficacy and Safety of Midostaurin in Advanced Systemic Mastocytosis. N Eng J Med. 2016; 374:2530-2541.

This study was reportedly the largest and longest-running prospective clinical trial ever in this disease, according to a statement from Novartis, the company manufacturing the agent. The FDA granted a breakthrough therapy designation status for midostaurin for a subset of adults with acute myeloid leukemia (AML) in January 2016 and an orphan drug status for AML and mastocytosis.